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Cyclin-dependent Kinase 6 Is the Principal Target of p27/Kip1 Regulation of the G₁-phase Traverse in 1,25-Dihydroxyvitamin D₃-treated HL60 Cells¹

Department of Pathology and Laboratory Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey 07103

Control of cell proliferation remains of intense interest in cancer research. In the 1,25-dihydroxyvitamin D₃ HL60 cell system, G₁ arrest has been shown to be mediated by elevated levels of p27/Kip1 protein. We show here that the main target of the elevated p27/Kip1 in this system is cyclin-dependent kinase (Cdk) 6. The activity of Cdk2 is also down-regulated, and this is associated with altered and reduced levels of cyclin E in the kinase complex. Paradoxically, the kinase activity of Cdk4 is elevated, in spite of an almost complete G₁ block. These data show that the functions of Cdk4 and Cdk6 are not redundant and that Cdk6 and Cdk2 activities are regulated by 1,25-dihydroxyvitamin D₃.

¹ Supported by USPHS Grant RO1-44722 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Department of Pathology and Laboratory Medicine, UMD-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103. Phone: (973) 972-5869; Fax: (973) 972-7293.

Received 4/ 2/97. Revised 5/13/97. Accepted 5/29/97.

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